Morphinan compounds

ABSTRACT

This invention relates to novel morphinan compounds and pharmaceutically acceptable salts thereof. This invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering a σ 1  receptor agonist that also has NMDA antagonist activity.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/546,173, filed Nov. 18, 2014, which is a continuation of U.S. patentapplication Ser. No. 14/208,968, filed Mar. 13, 2014 (now U.S. Pat. No.8,916,582), which is a continuation of U.S. patent application Ser. No.13/119,905, filed Jul. 1, 2011 (now U.S. Pat. No. 8,710,072), which is aNational Stage application under 35 U.S.C. §371 of InternationalApplication No. PCT/US2009/057476, filed Sep. 18, 2009, which claimspriority to U.S. Provisional Application Ser. No. 61/098,511, filed Sep.19, 2008, all of which are incorporated by reference herein in theirentireties.

TECHNICAL FIELD

This invention relates to novel morphinan compounds and pharmaceuticallyacceptable salts thereof. This invention also provides compositionscomprising a compound of this invention and the use of such compositionsin methods of treating diseases and conditions that are beneficiallytreated by administering a sigma-1 receptor agonist that also has NMDAantagonist activity.

BACKGROUND

Dextromethorphan, also known by its chemical name(+)-3-methoxy-17-methyl-(9α,13α,14α)-morphinan, is currently one of themost widely used antitussives.

In addition to the physiological activity noted above, dextromethorphanis also an agonist of the σ2 receptor, an N-methyl-D-aspartate (NMDA)antagonist, and an α3β4 nicotinic receptor antagonist. Dextromethorphaninhibits neurotransmitters, such as glutamate, from activating receptorsin the brain. Uptake of dopamine and serotonin are also inhibited.

Dextromethorphan is approved for use in over the counter coughsuppressant products. It is currently in Phase I clinical trials fortreating subjects with voice spasms, and Phase III clinical studies fortreating Rett Syndrome (http://www.clinicaltrials.gov). Dextromethorphanis being studied with other drugs in a Phase II clinical trialcharacterizing pain processing mechanisms in subjects with irritablebowel syndrome (http://www.clinicaltrials.gov/). Dextromethorphan isalso in Phase I clinical trials for treating hyperalgesia inmethadone-maintained subjects (http://www.clinicaltrials.gov/).

In addition, a combination of dextromethorphan hydrobromide andquinidine sulfate is currently in Phase III clinical trials for treatingdiabetic neuropathic pain (http://www.clinicaltrials.gov). This drugcombination, also know as Zenvia®, is in Phase III clinical trials fortreating Involuntary Emotional Expression Disorder (IEED), also known aspseudobulbar affect, in subjects suffering from Alzheimer's disease,stroke, Parkinson's disease and traumatic brain injury(http://www.clinicaltrials.gov).

Dextromethorphan is metabolized in the liver. Degradation begins with O-and N-demethylation to form primary metabolites dextrorphan and3-methoxy-morphinan, both of which are further N- and O-demethylatedrespectively to 3-hydroxy-morphinan. These three metabolites arebelieved to be therapeutically active. A major metabolic catalyst is thecytochrome P450 enzyme 2D6 (CYP2D6), which is responsible for theO-demethylation reactions of dextromethorphan and 3-methoxymorphinan.N-demethylation of dextromethorphan and dextrorphan are catalyzed byenzymes in the related CYP3A family. Conjugates of dextrorphan and3-hydroxymorphinan can be detected in human plasma and urine withinhours of its ingestion.

Dextromethorphan abuse has been linked to its active metabolite,dextrorphan. The PCP-like effects attributed to dextromethorphan aremore reliably produced by dextrorphan and thus abuse potential in humansmay be attributable to dextromethorphan metabolism to dextrorphan.(Miller, S C et al., Addict Biol, 2005, 10(4): 325-7., Nicholson, K L etal., Psychopharmacology (Berl), 1999 Sep. 1, 146(1): 49-59., Pender, E Set al., Pediatr Emerg Care, 1991, 7: 163-7). One study on thepsychotropic effects of dextromethorphan found that people who areextensive metabolizers (EM's) reported a greater abuse potentialcompared to poor metabolizers (PM's) providing evidence that dextrorphancontributes to dextromethorphan abuse potential (Zawertailo L A, et al.,J Clin Psychopharmacol, 1998 Aug., 18(4): 332-7).

A significant fraction of the population has a functional deficiency inthe CYP2D6 enzyme. Thus, because the major metabolic pathway fordextromethorphan requires CYP2D6, the decreased activity results in muchgreater duration of action and greater drug effects in CYP2D6-deficientsubjects. In addition to intrinsic functional deficiency, certainmedications, such as antidepressants, are potent inhibitors of theCYP2D6 enzyme. With its slower metabolism in some people,dextromethorphan, especially in combination with other medication(s),can lead to serious adverse events.

A longer than recommended duration of a drug in the body may providecontinued beneficial effects, but it may also create or prolongundesired side effects. Undesirable side effects at recommended doses ofdextromethorphan therapy include nausea, loss of appetite, diarrhea,drowsiness, dizziness, and impotence.

Dimemorfan, an analog of dextromethorphan, also known by its chemicalname as (+)-(9α,13α,14α)-3,17-dimethylmorphinan, is a non-narcoticantitussive. The antitussive activity of dimemorfan is believed toresult from direct action on the cough center in the medulla (Ida, H.,Clin Ther., 1997, March-April; 19(2): 215-31).

In addition to its antitussive properties, dimemorfan has been shown tohave anticonvulsant and neuroprotective effects possibly arising fromN-methyl-D-aspartate (NMDA) antagonism of dextromethorphan (DM) and/orhigh-affinity DM σ receptors (Chou, Y-C. et al., Brain Res., 1999, Mar.13; 821(2): 516-9). Activation at the σ-1 receptor has been found toprovide anticonvulsant action in rats and mice, like DM, but without thebehaviorial side effects produced by DM and its metabolite, dextrorphan(Shin, E. J. et al., Br J Pharmacol., 2005, April; 144(7): 908-18 andShin, E. J. et al., Behavioural Brain Research, 2004, 151: 267-276).

Metabolism of dimemorfan in humans is known to proceed throughcytochrome P450 catalyzed N-demethylation as well as 3-methyl oxidation.Greater than 98% of a dose of dimemorfan is metabolized in healthy humanmales and none of the metabolites have been shown to have antitussiveeffects (Chou Y-C., et al., Life Sci., 2005, Jul. 1; 77(7): 735-45 andChou Y-C., et al., J Pharm Sci., 2009, Jul. 1-15).

Additionally, two ether analogs of dextromethorphan,[(+)-3-ethoxy-17-methylmorphinan]also referred to herein as“dextroethorphan,” and [(+)-3-(2-propoxy)-17-methyl-morphinan]alsoreferred to herein as “dextroisoproporphan,” have shown anticonvulsantactivity (Newman, A. et al., J Med Chem., 1992, 35(22): 4135-42 andTortella, F. et al., J Pharmacol and Exp Therap., 1994, 268(2): 727-733)as well as neuroprotective effects in rats (Tortella, F. et al.,Neurosci. Lett., 1995, 198(2): 79-82).

Accordingly, it is desirable to provide new compounds that have thebeneficial activities of dextromethorphan, dimemorfan, dextroethorphanand dextroisoproporphan and may also have other benefits, e.g., reducedadverse side effects, with a decreased metabolic liability to furtherextend its pharmacological effective life, enhance subject complianceand, potentially, to decrease population pharmacokinetic variabilityand/or decrease its potential for dangerous drug-drug interactions ordecrease the likelihood of dextromethorphan abuse due to the formationof untoward metabolites such as dextrorphan.

SUMMARY

Provided herein is a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from —O—(C₂-C₄)alkyl and —(C₁-C₄)alkyl, wherein R¹ isoptionally substituted with one or more deuterium atoms; and

R² is selected from CH₃, CH₂D, CHD₂, and CD₃;

provided that at least one deuterium atom is present at either R¹ or R².

In some embodiments, R² is CH₃ or CD₃. In some embodiments, R¹ is—O—CH₂CH₃, —O—CD₂CD₃, —O—CD₂CH₃, —O—CH₂CD₃, —O—CH(CH₃)₂, —O—CD(CD₃)₂,—O—CH(CD₃)₂, —O—CD(CH₃)₂, —O—CH₂CH(CH₃)₂, —O—CD₂CH(CH₃)₂,—O—CH₂CD(CH₃)₂, —O—CH₂CH(CD₃)₂, —O—CD₂CD(CH₃)₂, —O—CD₂CH(CD₃)₂,—O—CH₂CD(CD₃)₂, or —O—CD₂CD(CD₃)₂.

In some embodiments R¹ is —O—(C₂-C₄)alkyl substituted with one or moredeuterium atoms.

In some embodiments, R¹ is —O—CD₂CD₃, —O—CD₂CH₃, —O—CH₂CD₃, —O—CD(CD₃)₂,—O—CH(CD₃)₂, —O—CD(CH₃)₂, —O—CD₂CH(CH₃)₂, —O—CH₂CD(CH₃)₂,—O—CH₂CH(CD₃)₂, —O—CD₂CD(CH₃)₂, —O—CD₂CH(CD₃)₂, —O—CH₂CD(CD₃)₂, or—O—CD₂CD(CD₃)₂.

In some embodiments, R¹ is —O—CD₂CD₃, —O—CD₂CH₃, —O—CH₂CD₃, —O—CD(CD₃)₂,—O—CH(CD₃)₂, or —O—CD(CH₃)₂.

In some embodiments, R¹ is —O—CD₂CD₃ or —O—CD(CD₃)₂.

In some embodiments, R¹ is —O—CD(CD₃)₂.

In some embodiments, a Formula I compound is selected from any one ofthe compounds in Table 1 set forth below:

Compound No. R¹ R² 100 —O—CD₂CD₃ CD₃ 101 —O—CD₂CH₃ CD₃ 102 —O—CD(CD₃)₂CD₃ 103 —O—CD(CH₃)₂ CD₃ 104 —O—CD₂CD₃ CH₃ 105 —O—CD₂CH₃ CH₃ 106—O—CD(CD₃)₂ CH₃ 107 —O—CD(CH₃)₂ CH₃

In some embodiments of the compound of Formula 1, R¹ is —(C₁-C₄)alkylwhich is optionally substituted with one or more deuterium atoms. Insome of these embodiments, R² is CH₃ or CD₃. In some of theseembodiments, R¹ is —CH₃, —CD₃, —CH₂CH₃, —CD₂CD₃, —CD₂CH₃, —CH₂CD₃,—CH(CH₃)₂, —CD(CD₃)₂, —CH(CD₃)₂, —CD(CH₃)₂, —CH₂CH(CH₃)₂, —CD₂CH(CH₃)₂,—CH₂CD(CH₃)₂, —CH₂CH(CD₃)₂, —CD₂CD(CH₃)₂, —CD₂CH(CD₃)₂, —CH₂CD(CD₃)₂, or—CD₂CD(CD₃)₂. In some of these embodiments, R¹ is —CD₃, —CD₂CD₃,—CD₂CH₃, —CH₂CD₃, —CD(CD₃)₂, —CH(CD₃)₂, —CD(CH₃)₂, —CD₂CH(CH₃)₂,—CH₂CD(CH₃)₂, —CH₂CH(CD₃)₂, —CD₂CD(CH₃)₂, —CD₂CH(CD₃)₂, —CH₂CD(CD₃)₂, or—CD₂CD(CD₃)₂. In some of these embodiments, R¹ is —CD₃, —CD₂CD₃, or—CD₂CD(CD₃)₂. In some of these embodiments, R¹ is —CD₃. In some of theseembodiments, R¹ is —CH₃, —CH₂CH₃, —CH(CH₃)₂, or —CH₂CH(CH₃)₂ and R² isselected from CD₃.

In some embodiments, the compound of Formula I is selected from any oneof:

In some embodiments of the compounds of Formula I, any atom notdesignated as deuterium is present at its natural isotopic abundance.

Also provided is a pyrogen-free pharmaceutical composition comprising acompound of Formula I and a pharmaceutically acceptable carrier. In someembodiments, the composition further comprises a second therapeuticagent useful in treating a patient suffering from or susceptible to adisease or condition selected from emotional lability; pseudobulbaraffect; autism; neurological disorders; neurodegenerative diseases;brain injury; disturbances of consciousness disorders; cardiovasculardiseases; glaucoma; tardive dyskinesia; diabetic neuropathy;retinopathic diseases; diseases or disorders caused byhomocysteine-induced apoptosis; diseases or disorders caused by elevatedlevels of homocysteine; pain, including but not limited to, chronicpain; intractable pain; neuropathic pain; sympathetically mediated pain;and pain associated with gastrointestinal dysfunction; epilepticseizures; tinnitus; sexual dysfunction; intractable coughing;dermatitis; addiction disorders; Rett syndrome (RTT); voice disordersdue to uncontrolled laryngeal muscle spasms; methotrexate neurotoxicity;fatigue caused by cancer; and conditions related to exposure to chemicalagents. Such chemical agents may include toxic agents such as, forexample, (i) agents used in warfare or combat, such as for example nervegas, or (ii) industrial pollutants.

In some embodiments, the second therapeutic agent is selected fromquinidine, quinidine sulfate, oxycodone, and gabapentin.

Also provided is a method of treating a subject suffering from orsusceptible to a disease or condition selected from emotional lability;pseudobulbar affect; autism; neurological disorders; neurodegenerativediseases; brain injury; disturbances of consciousness disorders;cardiovascular diseases; glaucoma; tardive dyskinesia; diabeticneuropathy; retinopathic diseases; diseases or disorders caused byhomocysteine-induced apoptosis; diseases or disorders caused by elevatedlevels of homocysteine; pain, including but not limited to, chronicpain; intractable pain; neuropathic pain; sympathetically mediated pain;and pain associated with gastrointestinal dysfunction; epilepticseizures; tinnitus; sexual dysfunction; intractable coughing;dermatitis; addiction disorders; Rett syndrome (RTT); voice disordersdue to uncontrolled laryngeal muscle spasms; methotrexate neurotoxicity;fatigue caused by cancer; and conditions related to exposure to chemicalagents, comprising the step of administering to the subject in needthereof a therapeutically effective amount of a pharmaceuticalcomposition comprising a compound of Formula I. In some embodiments, thesubject is suffering from or susceptible to diabetic neuropathic pain.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the metabolic stability of compounds of this invention inCYP2D6 SUPERSOMES™.

FIG. 2, panels A and B, depict the metabolic stability ofdextroethorphan (panel A), dextroisoproporphan (panel B), and compoundsof this invention in human liver microsomes.

FIG. 3 depicts the metabolic stability of dimemorfan and of compounds ofthis invention in human liver microsomes.

DETAILED DESCRIPTION Definitions

The terms “ameliorate” and “treat” are used interchangeably and includeboth therapeutic treatment and/or prophylactic treatment (reducing thelikelihood of development). Both terms mean decrease, suppress,attenuate, diminish, arrest, or stabilize the development or progressionof a disease (e.g., a disease or disorder delineated herein), lessen theseverity of the disease or improve the symptoms associated with thedisease.

“Disease” means any condition or disorder that damages or interfereswith the normal function of a cell, tissue, or organ.

It will be recognized that some variation of natural isotopic abundanceoccurs in a synthesized compound depending upon the origin of chemicalmaterials used in the synthesis. Thus, a preparation of dextromethorphanor dextromethorphan analogs will inherently contain small amounts ofdeuterated isotopologues. The concentration of naturally abundant stablehydrogen and carbon isotopes, notwithstanding this variation, is smalland immaterial as compared to the degree of stable isotopic substitutionof compounds of this invention. See, for instance, Wada E et al.,Seikagaku 1994, 66:15; Gannes L Z et al., Comp Biochem Physiol MolIntegr Physiol 1998, 119:725. Unless otherwise stated, when a positionis designated specifically as “H” or “hydrogen”, the position isunderstood to have hydrogen at its natural abundance isotopiccomposition. Also unless otherwise stated, when a position is designatedspecifically as “D” or “deuterium”, the position is understood to havedeuterium at an abundance that is at least 3340 times greater than thenatural abundance of deuterium, which is 0.015% (i.e., the term “D” or“deuterium” indicates at least 50.1% incorporation of deuterium).

The term “isotopic enrichment factor” as used herein means the ratiobetween the isotopic abundance of D at a specified position in acompound of this invention and the naturally occurring abundance of thatisotope. The natural abundance of deuterium is 0.015%.

In other embodiments, a compound of this invention has an isotopicenrichment factor for each deuterium present at a site designated as apotential site of deuteration on the compound of at least 3500 (52.5%deuterium incorporation), at least 4000 (60% deuterium incorporation),at least 4500 (67.5% deuterium incorporation), at least 5000 (75%deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000(90% deuterium incorporation), at least 6333.3 (95% deuteriumincorporation), at least 6466.7 (97% deuterium incorporation), at least6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuteriumincorporation). It is understood that the isotopic enrichment factor ofeach deuterium present at a site designated as a site of deuteration isindependent of other deuterated sites. For example, if there are twosites of deuteration on a compound one site could be deuterated at 52.5%while the other could be deuterated at 75%. The resulting compound wouldbe considered to be a compound wherein the isotopic enrichment factor isat least 3500 (52.5%).

The term “isotopologue” refers to a species that has the same chemicalstructure and formula as a specific compound of this invention, with theexception of the positions of isotopic substitution and/or level ofisotopic enrichment at one or more positions, e.g., H vs. D.

The term “compound,” as used herein, refers to a collection of moleculeshaving an identical chemical structure, except that there may beisotopic variation among the constituent atoms of the molecules. Thus,it will be clear to those of skill in the art that a compoundrepresented by a particular chemical structure containing indicateddeuterium atoms, will also contain lesser amounts of isotopologueshaving hydrogen atoms at one or more of the designated deuteriumpositions in that structure. The relative amount of such isotopologuesin a compound of this invention will depend upon a number of factorsincluding the isotopic purity of deuterated reagents used to make thecompound and the efficiency of incorporation of deuterium in the varioussynthesis steps used to prepare the compound. However, as set forthabove the relative amount of such isotopologues will be less than 49.9%of the compound.

A salt of a compound of this invention is formed between an acid and abasic group of the compound, such as an amino functional group, or abase and an acidic group of the compound, such as a carboxyl functionalgroup. According to another embodiment, the compound is apharmaceutically acceptable acid addition salt.

The term “pharmaceutically acceptable,” as used herein, refers to acomponent that is, within the scope of sound medical judgment, suitablefor use in contact with the tissues of humans and other mammals withoutundue toxicity, irritation, allergic response and the like, and arecommensurate with a reasonable benefit/risk ratio. A “pharmaceuticallyacceptable salt” means any suitable salt that, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound of this invention. A “pharmaceutically acceptable counterion”is an ionic portion of a salt that is not toxic when released from thesalt upon administration to a recipient.

Acids commonly employed to form pharmaceutically acceptable saltsinclude inorganic acids such as hydrogen bisulfide, hydrochloric acid,hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, aswell as organic acids such as para-toluenesulfonic acid, salicylic acid,tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylicacid, fumaric acid, gluconic acid, glucuronic acid, formic acid,glutamic acid, methanesulfonic acid, ethanesulfonic acid,benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonicacid, carbonic acid, succinic acid, citric acid, benzoic acid and aceticacid, as well as related inorganic and organic acids. Suchpharmaceutically acceptable salts thus include sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, propionate, decanoate, caprylate, acrylate, formate,isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate,succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate,hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate,terephthalate, sulfonate, xylene sulfonate, phenylacetate,phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate,glycolate, maleate, tartrate, methanesulfonate, propanesulfonate,naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and othersalts. In one embodiment, pharmaceutically acceptable acid additionsalts include those formed with mineral acids such as hydrochloric acidand hydrobromic acid, and especially those formed with organic acidssuch as maleic acid.

The term “stable compounds,” as used herein, refers to compounds whichpossess stability sufficient to allow for their manufacture and whichmaintain the integrity of the compound for a sufficient period of timeto be useful for the purposes detailed herein (e.g., formulation intotherapeutic products, intermediates for use in production of therapeuticcompounds, isolatable or storable intermediate compounds, treating adisease or condition responsive to therapeutic agents).

“Stereoisomer” refers to both enantiomers and diastereomers. “D” refersto deuterium. “Tert”, “^(t)”, and “t” each refer to tertiary. “US”refers to the United States of America. “FDA” refers to Food and DrugAdministration. “NDA” refers to New Drug Application. “rt” and “RT”refer to room temperature. “h” refers to hours. “DMF” refers todimethylformamide. “TsOH” refers to p-toluenesulfonic acid.

Throughout this specification, a variable may be referred to generally(e.g., “each R”) or may be referred to specifically (e.g., R¹ or R²).Unless otherwise indicated, when a variable is referred to generally, itis meant to include all specific embodiments of that particularvariable.

Therapeutic Compounds

The present invention provides a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is —O—(C₂-C₄)alkyl or —(C₁-C₄)alkyl, wherein R¹ is optionallysubstituted with one or more deuterium atoms; and

R² is CH₃, CH₂D, CHD₂, or CD₃;

provided that at least one deuterium atom is present at either R¹ or R².

The preferred stereochemistry of the present compounds is based on thestereochemistry of morphinan compounds such as dextromethorphan, whichexists as the dextrorotatory enantiomer of levorphanol.

One embodiment of the invention provides a compound of Formula I whereinR¹ is —O—(C₂-C₄)alkyl which is optionally substituted with one or moredeuterium atoms. In one aspect of this embodiment, R¹ is —O—CH₂CH₃,—O—CD₂CD₃, —O—CD₂CH₃, —O—CH₂CD₃, —O—CH(CH₃)₂, —O—CD(CD₃)₂, —O—CH(CD₃)₂,—O—CD(CH₃)₂, —O—CH₂CH(CH₃)₂, —O—CD₂CH(CH₃)₂, —O—CH₂CD(CH₃)₂,—O—CH₂CH(CD₃)₂, —O—CD₂CD(CH₃)₂, —O—CD₂CH(CD₃)₂, —O—CH₂CD(CD₃)₂, or—O—CD₂CD(CD₃)₂.

In another aspect, R¹ is —O—CD₂CD₃, —O—CD₂CH₃, —O—CH₂CD₃, —O—CD(CD₃)₂,—O—CH(CD₃)₂, —O—CD(CH₃)₂, —O—CD₂CH(CH₃)₂, —O—CH₂CD(CH₃)₂,—O—CH₂CH(CD₃)₂, —O—CD₂CD(CH₃)₂, —O—CD₂CH(CD₃)₂, —O—CH₂CD(CD₃)₂, or—O—CD₂CD(CD₃)₂.

In another aspect, R¹ is —O—CD₂CD₃, —O—CD₂CH₃, —O—CH₂CD₃, —O—CD(CD₃)₂,—O—CH(CD₃)₂, or —O—CD(CH₃)₂.

In another aspect, R¹ is —O—CD₂CD₃ or —O—CD(CD₃)₂. In another aspect, R¹is —O—CD₂CD₃.

In another aspect, R¹ is —O—CD(CD₃)₂.

Another embodiment of Formula I provides a compound of Formula I whereinR¹ is a deuterated —O—(C₂-C₄)alkyl and R² is —CD₃ or —CH₃. In one aspectof this embodiment, R² is —CD₃. In another aspect R² is —CH₃.

Each of the above aspects of R¹ may be combined with each of the aboveaspects of R² to form further embodiments of this invention.

Examples of specific compounds where R¹ is —O—(C₂-C₄)alkyl include thoseshown in Table 1:

TABLE 1 Exemplary Compounds of Formula I (R¹ is —O—(C₂—C₄)alkyl)Compound No. R¹ R² 100 —O—CD₂CD₃ CD₃ 101 —O—CD₂CH₃ CD₃ 102 —O—CD(CD₃)₂CD₃ 103 —O—CD(CH₃)₂ CD₃ 104 —O—CD₂CD₃ CH₃ 105 —O—CD₂CH₃ CH₃ 106—O—CD(CD₃)₂ CH₃ 107 —O—CD(CH₃)₂ CH₃

or a pharmaceutically acceptable salt thereof.

Another embodiment of this invention provides compounds of Formula Iwherein R¹ is —(C₁-C₄)alkyl which is optionally substituted with one ormore deuterium atoms. In one aspect of this embodiment, R¹ is —CH₃,—CD₃, —CH₂CH₃, —CD₂CD₃, —CD₂CH₃, —CH₂CD₃, —CH₂CH₂CH₃, —CD₂CH₂CH₃,—CD₂CD₂CH₃, —CD₂CD₂CD₃, —CH₂CD₂CH₃, —CH₂CD₂CD₃, —CH₂CH₂CD₃, —CH(CH₃)₂,—CD(CD₃)₂, —CH(CD₃)₂, —CD(CH₃)₂, —CH₂CH₂CH₂CH₃, —CD₂CH₂CH₂CH₃,—CD₂CD₂CH₂CH₃, —CD₂CD₂CD₂CH₃, —CD₂CD₂CD₂CD₃, —CD₂CH₂CD₂CH₃,—CD₂CH₂CH₂CD₃, —CD₂CH₂CD₂CD₃, —CH₂CD₂CH₂CH₃, —CH₂CH₂CD₂CH₃,—CH₂CH₂CH₂CD₃, —CH₂CD₂CD₂CH₃, —CH₂CD₂CH₂CD₃, —CH₂CH₂CD₂CD₃,—CH(CH₃)CH₂CH₃, —CD(CH₃)CH₂CH₃, —CD(CD₃)CH₂CH₃, —CD(CD₃)CD₂CH₃,—CD(CD₃)CD₂CD₃, —CD(CH₃)CD₂CH₃, —CD(CH₃)CD₂CH₃, —CD(CH₃)CH₂CD₃,—CH(CD₃)CH₂CH₃, —CH(CH₃)CD₂CH₃, —CH(CH₃)CH₂CD₃, —CH(CD₃)CD₂CH₃,CH(CD₃)CH₂CD₃, —CH(CH₃)CD₂CD₃, —CH₂CH(CH₃)₂, —CD₂CH(CH₃)₂, —CH₂CD(CH₃)₂,—CH₂CH(CD₃)₂, —CD₂CD(CH₃)₂, —CD₂CH(CD₃)₂, —CH₂CD(CD₃)₂, or —CD₂CD(CD₃)₂.In another aspect, R¹ is —CH₃, —CH₂CH₃, —CH(CH₃)₂, or —CH₂CH(CH₃)₂ andR² is selected from CD₃. In another aspect, R¹ is —CD₃, —CD₂CD₃,—CD₂CH₃, —CH₂CD₃, —CD(CD₃)₂, —CH(CD₃)₂, —CD(CH₃)₂, —CD₂CH(CH₃)₂,—CH₂CD(CH₃)₂, —CH₂CH(CD₃)₂, —CD₂CD(CH₃)₂, —CD₂CH(CD₃)₂, —CH₂CD(CD₃)₂, or—CD₂CD(CD₃)₂. In another aspect, R¹ is —CD₃, —CD₂CD₃, or —CD₂CD(CD₃)₂.In another aspect, R¹ is —CD₃. Each of these aspects of R¹ may becombined with the below aspects of R² to provide further embodiments ofthis invention.

Another embodiment of this invention provides compounds of Formula Iwherein R¹ is a deuterated —(C₁-C₄)alkyl and wherein R² is —CH₃ or —CD₃.In one aspect of this embodiment, R² is —CH₃. In another aspect, R² is—CD₃.

Examples of specific compounds of Formula I where R¹ is —(C₁-C₄)alkylinclude Compounds 108, 109 and 110 shown below:

or a pharmaceutically acceptable salt thereof.

In another set of embodiments, any atom not designated as deuterium inany of the embodiments set forth above is present at its naturalisotopic abundance.

In another set of embodiments, the compound of Formula I is purified,e.g., the compound of Formula I is present at a purity of at least 50.1%by weight (e.g., at least 52.5%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,95%, 97%, 98%, 98.5%, 99%, 99.5% or 99.9%) of the total amount ofisotopologues of Formula I present, respectively. Thus, in someembodiments, a composition comprising a compound of Formula I caninclude a distribution of isotopologues of the compound, provided atleast 50.1% of the isotopologues by weight are the recited compound.

In another set of embodiments, the compounds of Formula I are providedin isolated form, e.g., the compound is not in a cell or organism andthe compound is separated from some or all of the components thattypically accompany it in nature.

In some embodiments, any position in the compound of Formula Idesignated as having D has a minimum deuterium incorporation of at least50.1% (e.g., at least 52.5%, at least 60%, at least 67.5%, at least 75%,at least 82.5%, at least 90%, at least 95%, at least 97%, at least 99%,or at least 99.5%) at the designated position(s) of the compound ofFormula I. Thus, in some embodiments, a composition comprising acompound of Formula I can include a distribution of isotopologues of thecompound, provided at least 50.1% of the isotopologues include a D atthe designated position(s).

In some embodiments, a compound of Formula I is “substantially free of”other isotopologues of the compound, e.g., less than 49.9%, less than25%, less than 10%, less than 5%, less than 2%, less than 1%, or lessthan 0.5% of other isotopologues are present.

The synthesis of compounds of Formula I can be readily achieved byreference to the Exemplary Syntheses and Examples disclosed herein, andby use of procedures and intermediates analogous to those disclosed, forinstance, in Schnider, O. & Grussner, A., Helv. Chim. Acta., 1951, 34:2211; Grussner, A. & Schnider, O.; GB 713146 (1954); Toyo Pharma K. K.,Japan JP 60089474 A (1983); Newman, A. H. et al., J. Med. Chem., 1992,35: 4135. Such methods can be carried out by utilizing correspondingdeuterated and, optionally, other isotope-containing reagents and/orintermediates to synthesize the compounds delineated herein, or byinvoking standard synthetic protocols known in the art for introducingisotopic atoms to a chemical structure.

Exemplary Syntheses

The following deuterated reagents and building blocks which may be ofuse in preparing compounds of Formula I are commercially available:iodoethane-d₅, ethyl-2,2,2-d₃ iodide, ethyl-1,1-d₂ iodide, isopropyl-d₇iodide, isopropyl-d₇ bromide, isopropyl-1,1,1,3,3,3-d₆ iodide, and1,1,1,3,3,3-d₆ bromide.

A convenient method for synthesizing compounds of Formula I wherein R¹is —O—(C₂-C₄)alkyl is depicted in Scheme 1.

Treatment of the known 17-ethoxycarbonyl-3-methoxy-morphinan (10) (forits preparation, see: Murdter, T. E. et al., Journal of LabelledCompounds and Radiopharmaceuticals 2002, 45: 1153-1158) with borontribromide according to the procedure described by Newman, A. H. et al.,Journal of Medicinal Chemistry 1992, 35: 4135-4142, affords the17-ethoxycarbonyl-3-hydroxy-morphinan (11). Treatment of the3-hydroxy-morphinan 11 with the appropriately deuterated alkyl iodide inthe presence of potassium carbonate in a manner analogous to theprocedure described in the aforementioned paper gives the deuterated17-ethoxycarbonyl-3-alkoxy-morphinans (12). Reduction of the carbamateof the morphinan 12 with either lithium aluminum hydride or lithiumaluminum deuteride in THF in a manner analogous to that described byNewman affords the deuterated 3-alkoxy-17-methyl-morphinan (13) or the3-alkoxy-17-trideuteromethyl-morphinan (14) compounds of Formula I,respectively.

A convenient method for synthesizing compounds of Formula I wherein R¹is —(C₁-C₄)alkyl is depicted in Scheme 2.

Treatment of 17-ethoxycarbonyl-3-hydroxy-morphinan (11) withN-Phenyl-trifluoromethanesulfonimide according to the proceduredescribed by Kim, C.-H. in US 2005/0256147 A1 affords the correspondingphenolic triflate (15). Palladium catalyzed cross-coupling of 15 withthe appropriately deuterated (C₁-C₄)alkyl boronic acid (16) in a manneranalogous to the procedure from the aforementioned patent gives thedeuterated 17-ethoxycarbonyl-3-(C₁-C₄)alkyl-morphinans (17). Reductionof the carbamate of morphinan 17 with either lithium aluminum hydride orlithium aluminum deuteride in THF in a manner analogous to the proceduredescribed by Newman, A. H. et al., Journal of Medicinal Chemistry 1992,35: 4135-4142 affords the deuterated 3-(C₁-C₄)alkyl-17-methyl-morphinanor the 3-(C₁-C₄)alkyl-17-trideuteromethyl-morphinan compounds of FormulaI, respectively.

The alkylboronic acid reagent 16 used in Scheme 2 is prepared asdescribed above in Scheme 3.

Treatment of appropriately deuterated (C₁-C₄)alkyl halide (20) withelemental lithium in pentane in a manner analogous to the proceduredescribed by Dawildowski, D. et al., in WO 2005/082911 A1 affords thecorresponding (C₁-C₄)alkyl lithium anion, which may be immediatelytreated with triisopropyl borate followed by hydrolysis with aqueoushydrogen chloride in a manner analogous to the procedure described byBrown, H. C. et al., Organometallics 1985, 4: 816-821 to afford theappropriately deuterated (C₁-C₄)alkyl boronic acids (16).

The specific approaches and compounds shown above are not intended to belimiting. The chemical structures in the schemes herein depict variablesthat are hereby defined commensurately with chemical group definitions(moieties, atoms, etc.) of the corresponding position in the compoundformulae herein, whether identified by the same variable name (i.e., R¹or R²) or not. The suitability of a chemical group in a compoundstructure for use in the synthesis of another compound is within theknowledge of one of ordinary skill in the art. Additional methods ofsynthesizing compounds of Formula I and their synthetic precursors,including those within routes not explicitly shown in schemes herein,are within the means of chemists of ordinary skill in the art. Syntheticchemistry transformations and protecting group methodologies (protectionand deprotection) useful in synthesizing the applicable compounds areknown in the art and include, for example, those described in Larock R,Comprehensive Organic Transformations, VCH Publishers (1989); Greene T Wet al., Protective Groups in Organic Synthesis, 3^(rd) Ed., John Wileyand Sons (1999); Fieser L et al., Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); and Paquette L, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995) and subsequent editions thereof.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds.

Compositions

The invention also provides pyrogen-free compositions comprising acompound of Formula I (e.g., including any of the formulae herein), or apharmaceutically acceptable salt of said compound; and an acceptablecarrier. In one embodiment, the composition comprises an effectiveamount of the compound or pharmaceutically acceptable salt thereof.Preferably, a composition of this invention is formulated forpharmaceutical use (“a pharmaceutical composition”), wherein the carrieris a pharmaceutically acceptable carrier. The carrier(s) are“acceptable” in the sense of being compatible with the other ingredientsof the formulation and, in the case of a pharmaceutically acceptablecarrier, not deleterious to the recipient thereof in an amount used inthe medicament.

Pharmaceutically acceptable carriers, adjuvants and vehicles that may beused in the pharmaceutical compositions of this invention include, butare not limited to, ion exchangers, alumina, aluminum stearate,lecithin, serum proteins, such as human serum albumin, buffer substancessuch as phosphates, glycine, sorbic acid, potassium sorbate, partialglyceride mixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

If required, the solubility and bioavailability of the compounds of thepresent invention in pharmaceutical compositions may be enhanced bymethods well-known in the art. One method includes the use of lipidexcipients in the formulation. See “Oral Lipid-Based Formulations:Enhancing the Bioavailability of Poorly Water-Soluble Drugs (Drugs andthe Pharmaceutical Sciences),” David J. Hauss, ed. Informa Healthcare,2007; and “Role of Lipid Excipients in Modifying Oral and ParenteralDrug Delivery: Basic Principles and Biological Examples,” Kishor M.Wasan, ed. Wiley-Interscience, 2006.

Another known method of enhancing bioavailability is the use of anamorphous form of a compound of this invention optionally formulatedwith a poloxamer, such as LUTROL™ and PLURONIC™ (BASF Corporation), orblock copolymers of ethylene oxide and propylene oxide. See U.S. Pat.No. 7,014,866; and United States patent publications 20060094744 and20060079502.

The pharmaceutical compositions of the invention include those suitablefor oral, rectal, nasal, topical (including buccal and sublingual),vaginal or parenteral (including subcutaneous, intramuscular,intravenous and intradermal) administration. In certain embodiments, thecompound of the formulae herein is administered transdermally (e.g.,using a transdermal patch or iontophoretic techniques). Otherformulations may conveniently be presented in unit dosage form, e.g.,tablets, sustained release capsules, and in liposomes, and may beprepared by any methods well known in the art of pharmacy. See, forexample, Remington: The Science and Practice of Pharmacy, LippincottWilliams & Wilkins, Baltimore, Md. (20th ed. 2000).

Such preparative methods include the step of bringing into associationwith the molecule to be administered ingredients such as the carrierthat constitutes one or more accessory ingredients. In general, thecompositions are prepared by uniformly and intimately bringing intoassociation the active ingredients with liquid carriers, liposomes orfinely divided solid carriers, or both, and then, if necessary, shapingthe product.

In certain embodiments, the compound is administered orally.Compositions of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, sachets, or tabletseach containing a predetermined amount of the active ingredient; apowder or granules; a solution or a suspension in an aqueous liquid or anon-aqueous liquid; an oil-in-water liquid emulsion; a water-in-oilliquid emulsion; packed in liposomes; or as a bolus, etc. Soft gelatincapsules can be useful for containing such suspensions, which maybeneficially increase the rate of compound absorption.

In the case of tablets for oral use, carriers that are commonly usedinclude lactose and corn starch. Lubricating agents, such as magnesiumstearate, are also typically added. For oral administration in a capsuleform, useful diluents include lactose and dried cornstarch. When aqueoussuspensions are administered orally, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweeteningand/or flavoring and/or coloring agents may be added.

Compositions suitable for oral administration include lozengescomprising the ingredients in a flavored basis, usually sucrose andacacia or tragacanth; and pastilles comprising the active ingredient inan inert basis such as gelatin and glycerin, or sucrose and acacia.

Compositions suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents. The formulations may be presented in unit-dose or multi-dosecontainers, for example, sealed ampules and vials, and may be stored ina freeze dried (lyophilized) condition requiring only the addition ofthe sterile liquid carrier, for example water for injections,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tablets.

Such injection solutions may be in the form, for example, of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to techniques known in the art using suitabledispersing or wetting agents (such as, for example, Tween 80) andsuspending agents. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example, as a solutionin 1,3-butanediol. Among the acceptable vehicles and solvents that maybe employed are mannitol, water, Ringer's solution and isotonic sodiumchloride solution. In addition, sterile, fixed oils are conventionallyemployed as a solvent or suspending medium. For this purpose, any blandfixed oil may be employed including synthetic mono- or diglycerides.Fatty acids, such as oleic acid and its glyceride derivatives are usefulin the preparation of injectables, as are naturalpharmaceutically-acceptable oils, such as olive oil or castor oil,especially in their polyoxyethylated versions. These oil solutions orsuspensions may also contain a long-chain alcohol diluent or dispersant.

The pharmaceutical compositions of this invention may be administered inthe form of suppositories for rectal administration. These compositionscan be prepared by mixing a compound of this invention with a suitablenon-irritating excipient which is solid at room temperature but liquidat the rectal temperature and therefore will melt in the rectum torelease the active components. Such materials include, but are notlimited to, cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of this invention may be administered bynasal aerosol or inhalation. Such compositions are prepared according totechniques well-known in the art of pharmaceutical formulation and maybe prepared as solutions in saline, employing benzyl alcohol or othersuitable preservatives, absorption promoters to enhance bioavailability,fluorocarbons, and/or other solubilizing or dispersing agents known inthe art. See, e.g.: Rabinowitz J D and Zaffaroni A C, U.S. Pat. No.6,803,031, assigned to Alexza Molecular Delivery Corporation.

Topical administration of the pharmaceutical compositions of thisinvention is especially useful when the desired treatment involves areasor organs readily accessible by topical application. For topicalapplication topically to the skin, the pharmaceutical composition shouldbe formulated with a suitable ointment containing the active componentssuspended or dissolved in a carrier. Carriers for topical administrationof the compounds of this invention include, but are not limited to,mineral oil, liquid petroleum, white petroleum, propylene glycol,polyoxyethylene polyoxypropylene compound, emulsifying wax, and water.Alternatively, the pharmaceutical composition can be formulated with asuitable lotion or cream containing the active compound suspended ordissolved in a carrier. Suitable carriers include, but are not limitedto, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esterswax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. Thepharmaceutical compositions of this invention may also be topicallyapplied to the lower intestinal tract by rectal suppository formulationor in a suitable enema formulation. Topically-transdermal patches andiontophoretic administration are also included in this invention.

Application of the subject therapeutics may be local, so as to beadministered at the site of interest. Various techniques can be used forproviding the subject compositions at the site of interest, such asinjection, use of catheters, trocars, projectiles, pluronic gel, stents,sustained drug release polymers or other device which provides forinternal access.

Thus, according to yet another embodiment, the compounds of thisinvention may be incorporated into compositions for coating animplantable medical device, such as prostheses, artificial valves,vascular grafts, stents, or catheters. Suitable coatings and the generalpreparation of coated implantable devices are known in the art and areexemplified in U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. Thecoatings are typically biocompatible polymeric materials such as ahydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethyleneglycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof.The coatings may optionally be further covered by a suitable topcoat offluorosilicone, polysaccharides, polyethylene glycol, phospholipids orcombinations thereof to impart controlled release characteristics in thecomposition. Coatings for invasive devices are to be included within thedefinition of pharmaceutically acceptable carrier, adjuvant or vehicle,as those terms are used herein.

According to another embodiment, the invention provides a method ofcoating an implantable medical device comprising the step of contactingsaid device with the coating composition described above. It will beobvious to those skilled in the art that the coating of the device willoccur prior to implantation into a mammal.

According to another embodiment, the invention provides a method ofimpregnating an implantable drug release device comprising the step ofcontacting said drug release device with a compound or composition ofthis invention. Implantable drug release devices include, but are notlimited to, biodegradable polymer capsules or bullets, non-degradable,diffusible polymer capsules and biodegradable polymer wafers.

According to another embodiment, the invention provides an implantablemedical device coated with a compound or a composition comprising acompound of this invention, such that said compound is therapeuticallyactive.

According to another embodiment, the invention provides an implantabledrug release device impregnated with or containing a compound or acomposition comprising a compound of this invention, such that saidcompound is released from said device and is therapeutically active.

Where an organ or tissue is accessible because of removal from thesubject, such organ or tissue may be bathed in a medium containing acomposition of this invention, a composition of this invention may bepainted onto the organ, or a composition of this invention may beapplied in any other convenient way.

In another embodiment, a composition of this invention further comprisesa second therapeutic agent. The second therapeutic agent may be selectedfrom any compound or therapeutic agent known to have or thatdemonstrates advantageous properties when administered with a compoundhaving the same mechanism of action as dextromethorphan. Such agentsinclude those indicated as being useful in combination withdextromethorphan, including but not limited to, those described in U.S.Pat. Nos. 4,316,888; 4,446,140; 4,694,010; 4,898,860; 5,166,207;5,336,980; 5,350,756; 5,366,980; 5,863,927; RE38,115; 6,197,830;6,207,164; 6,583,152; and 7,114,547; as well as in US patentpublications 2001/0044446; 2002/0103109; 2004/0087479; 2005/0129783;2005/0203125; and 2007/0191411.

Preferably, the second therapeutic agent is an agent useful in thetreatment or prevention of a disease or condition selected fromemotional lability; pseudobulbar affect; autism; neurological disordersand neurodegenerative diseases, such as, e.g., dementia, amyotrophiclateral sclerosis (ALS, also known as Leu Gehrig's disease), Alzheimer'sdisease, Parkinson's disease, and multiple sclerosis; brain injuries,such as, e.g., stroke, traumatic brain injury, ischemic event, hypoxicevent and neuronal death; disturbances of consciousness disorders;cardiovascular diseases, such as, e.g., peripheral vascular diseases,myocardial infarctions, and atherosclerosis; glaucoma, tardivedyskinesia; diabetic neuropathy; retinopathic diseases; diseases ordisorders caused by homocysteine-induced apoptosis; diseases ordisorders caused by elevated levels of homocysteine; chronic pain;intractable pain; neuropathic pain, sympathetically mediated pain, suchas, allodynia, hyperpathia, hyperalgesia, dysesthesia, paresthesia,deafferentation pain, and anesthesia dolorosa pain; pain associated withgastrointestinal dysfunction, including, e.g., irritable bowel syndrome;mouth pain; epileptic seizures; tinnitus; sexual dysfunction;intractable coughing; dermatitis; addiction disorders, such as, e.g.,addiction to or dependence on stimulants, nicotine, morphine, heroine,other opiates, amphetamines, cocaine, and alcohol; Rett syndrome (RTT);voice disorders due to uncontrolled laryngeal muscle spasms, includinge.g., abductor spasmodic dysphonia, adductor spasmodic dysphonia,muscular tension dysphonia, and vocal tremor; methotrexateneurotoxicity; and fatigue caused by cancer.

In one embodiment, the second therapeutic agent is selected fromquinidine, quinidine sulfate, LBH589 (Novartis), oxycodone, andgabapentin.

In another embodiment, the invention provides separate dosage forms of acompound of this invention and one or more of any of the above-describedsecond therapeutic agents, wherein the compound and second therapeuticagent are associated with one another. The term “associated with oneanother” as used herein means that the separate dosage forms arepackaged together or otherwise attached to one another such that it isreadily apparent that the separate dosage forms are intended to be soldand administered together (within less than 24 hours of one another,consecutively or simultaneously).

In one embodiment of the pharmaceutical compositions of the invention,the compound of the present invention is present in an effective amount.As used herein, the term “effective amount” refers to an amount which,when administered in a proper dosing regimen, is sufficient to reduce orameliorate the severity, duration or progression of the disorder beingtreated, prevent the advancement of the disorder being treated, causethe regression of the disorder being treated, or enhance or improve theprophylactic or therapeutic effect(s) of another therapy.

The interrelationship of dosages for animals and humans (based onmilligrams per meter squared of body surface) is described in Freireichet al., (1966) Cancer Chemother. Rep 50: 219. Body surface area may beapproximately determined from height and weight of the subject. See,e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 1970,537.

In one embodiment, an effective amount of a compound of this inventioncan range from 0.4 mg to 400 mg, from 4.0 mg to 350 mg, from 10 mg to 90mg, or from 30 mg to 45 mg, inclusive, which can be given once, twice,or up to three times daily depending on various factors recognized bythose skilled in the art.

Effective doses will also vary, as recognized by those skilled in theart, depending on the diseases treated, the severity of the disease, theroute of administration, the sex, age and general health condition ofthe subject, excipient usage, the possibility of co-usage with othertherapeutic treatments such as use of other agents and the judgment ofthe treating physician. For example, guidance for selecting an effectivedose can be determined by reference to the prescribing information fordextromethorphan.

For pharmaceutical compositions that comprise a second therapeuticagent, an effective amount of the second therapeutic agent is betweenabout 0.01% to 100% of the dosage normally utilized in a monotherapyregime using just that agent. The normal monotherapeutic dosages ofthese second therapeutic agents are well known in the art. See, e.g.,Wells et al., eds., Pharmacotherapy Handbook, 2nd Edition, Appleton andLange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon PocketPharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda,Calif. (2000), each of which references are incorporated herein byreference in their entirety.

It is expected that some of the second therapeutic agents referencedabove will act synergistically with the compounds of this invention.When this occurs, it will allow the effective dosage of the secondtherapeutic agent and/or the compound of this invention to be reducedfrom that required in a monotherapy. This has the advantage ofminimizing toxic side effects of either the second therapeutic agent ofa compound of this invention, synergistic improvements in efficacy,improved ease of administration or use and/or reduced overall expense ofcompound preparation or formulation.

Methods of Treatment

In another embodiment, the invention provides a method of modulating theactivity of the sigma-1 and sigma-2 receptor, N-methyl-D-aspartate(NMDA), or the activity of the α3β4 nicotinic receptor in a cell,comprising contacting a cell with one or more compounds of Formula I.

In another embodiment, the invention provides a method of inhibitingneurotransmitters, such as glutamate, from activating receptors in thebrain and/or inhibiting the uptake of dopamine and serotonin byadministering a compound of Formula I.

According to another embodiment, the invention provides a method oftreating a subject suffering from, or susceptible to, a disease orcondition that is beneficially treated by dextromethorphan comprisingthe step of administering to said subject an effective amount of acompound of Formula I or a pharmaceutically acceptable salt thereof or acomposition comprising such compound. Such diseases and conditions arewell known in the art and are disclosed in, but not limited to, thosedescribed in U.S. Pat. Nos. 4,316,888; 4,446,140; 4,694,010; 4,898,860;5,166,207; 5,336,980; 5,350,756; 5,366,980; 5,863,927; RE38,115;6,197,830; 6,207,164; 6,583,152; and 7,114,547; as well as in US patentpublications 2001/0044446; 2002/0103109; 2004/0087479; 2005/0129783;2005/0203125; and 2007/0191411.

Such diseases and conditions include, but are not limited to, emotionallability; pseudobulbar affect; autism; neurological disorders andneurodegenerative diseases, such as, e.g., dementia, amyotrophic lateralsclerosis (ALS, also known as Leu Gehrig's disease), Alzheimer'sdisease, and multiple sclerosis; disturbances of consciousnessdisorders; cardiovascular diseases, such as, e.g., peripheral vasculardiseases, strokes, myocardial infarctions, and atherosclerosis;glaucoma, tardive dyskinesia; diabetic neuropathy; retinopathicdiseases; diseases or disorders caused by homocysteine-inducedapoptosis; diseases or disorders caused by elevated levels ofhomocysteine; pain, including but not limited to, chronic pain;intractable pain; neuropathic pain, sympathetically mediated pain, suchas, allodynia, hyperpathia, hyperalgesia, dysesthesia, paresthesia,deafferentation pain, and anesthesia delorosa pain; pain associated withgastrointestinal dysfunction, including, e.g., irritable bowel syndrome;and mouth pain; epileptic seizures; tinnitus; sexual dysfunction;intractable coughing; dermatitis; addiction disorders, such as, e.g.,addiction to or dependence on stimulants, nicotine, morphine, heroine,other opiates, amphetamines, cocaine, and alcohol; Rett syndrome (RTT);voice disorders due to uncontrolled laryngeal muscle spasms, includinge.g., abductor spasmodic dysphonia, adductor spasmodic dysphonia,muscular tension dysphonia, and vocal tremor; methotrexateneurotoxicity; fatigue caused by cancer; and conditions related toexposure to chemical agents.

In one particular embodiment, the method of this invention is used totreat a subject suffering from or susceptible to a disease or conditionselected from diabetic neuropathy, Rett syndrome (RTT); voice disordersdue to uncontrolled laryngeal muscle spasms, including e.g., abductorspasmodic dysphonia, adductor spasmodic dysphonia, muscular tensiondysphonia, and vocal tremor; methotrexate neurotoxicity; and fatiguecaused by cancer.

In one particular embodiment, the method is used to treat a subjectsuffering from or susceptible neuropathic pain. In another embodiment,the method is used to treat a subject suffering from pseudobulbaraffect.

In another particular embodiment, the method is used to treat a subjectsuffering from generalized epileptic seizures or partial epilepticseizures.

Methods delineated herein also include those wherein the subject isidentified as in need of a particular stated treatment. Identifying asubject in need of such treatment can be in the judgment of a subject ora health care professional and can be subjective (e.g. opinion) orobjective (e.g. measurable by a test or diagnostic method).

In another embodiment, any of the above methods of treatment comprisesthe further step of co-administering to the subject one or moreadditional second therapeutic agents. The choice of second therapeuticagent may be made from any second therapeutic agent known to be usefulfor co-administration with dextromethorphan. The choice of secondtherapeutic agent is also dependent upon the particular disease orcondition to be treated. Examples of second therapeutic agents that maybe employed in the methods of this invention are those set forth abovefor use in combination compositions comprising a compound of thisinvention and a second therapeutic agent.

In particular, the combination therapies of this invention includeco-administering to a subject in need thereof a compound of Formula I orpharmaceutically acceptable salt thereof, or a composition comprisingsuch compound or salt; and quinidine sulfate wherein the subject issuffering from or susceptible to diabetic neuropathy.

In another embodiment the invention provides a method of treating asubject suffering from non-small cell lung cancer or malignant pleuralmesothelioma by co-administering to the subject in need thereof acompound of Formula I, or a composition comprising such compound; andLBH589.

The term “co-administered” as used herein means that the additionalsecond therapeutic agent may be administered together with a compound ofthis invention as part of a single dosage form (such as a composition ofthis invention comprising a compound of the invention and an secondtherapeutic agent as described above) or as separate, multiple dosageforms. Alternatively, the additional agent may be administered prior to,consecutively with, or following the administration of a compound ofthis invention. In such combination therapy treatment, both thecompounds of this invention and the second therapeutic agent(s) areadministered by conventional methods. The administration of acomposition of this invention, comprising both a compound of theinvention and a second therapeutic agent, to a subject does not precludethe separate administration of that same therapeutic agent, any othersecond therapeutic agent or any compound of this invention to saidsubject at another time during a course of treatment.

Effective amounts of these second therapeutic agents are well known tothose skilled in the art and guidance for dosing may be found in patentsand published patent applications referenced herein, as well as in Wellset al., eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange,Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000),and other medical texts. However, it is well within the skilledartisan's purview to determine the second therapeutic agent's optimaleffective-amount range.

In one embodiment of the invention, where a second therapeutic agent isadministered to a subject, the effective amount of the compound of thisinvention is less than its effective amount would be where the secondtherapeutic agent is not administered. In another embodiment, theeffective amount of the second therapeutic agent is less than itseffective amount would be where the compound of this invention is notadministered. In this way, undesired side effects associated with highdoses of either agent may be minimized. Other potential advantages(including without limitation improved dosing regimens and/or reduceddrug cost) will be apparent to those of skill in the art.

In yet another aspect, the invention provides the use of a compound ofFormula I alone or together with one or more of the above-describedsecond therapeutic agents in the manufacture of a medicament, either asa single composition or as separate dosage forms, for treatment orprevention in a subject of a disease, disorder or symptom set forthabove. Another aspect of the invention is a compound of Formula I foruse in the treatment or prevention in a subject of a disease, disorderor symptom thereof delineated herein.

Diagnostic Methods and Kits

The compounds and compositions of this invention are also useful asreagents in methods for determining the concentration ofdextromethorphan in solution or biological sample such as plasma,examining the metabolism of dextromethorphan and other analyticalstudies.

According to one embodiment, the invention provides a method ofdetermining the concentration, in a solution or a biological sample, ofa non-deuterated analog of a compound of Formula I, comprising the stepsof:

a) adding a known concentration of a compound of Formula I to thesolution of biological sample;

b) subjecting the solution or biological sample to a measuring devicethat distinguishes the corresponding non-deuterated analog from acompound of Formula I;

c) calibrating the measuring device to correlate the detected quantityof the compound of Formula I with the known concentration of thecompound of Formula I added to the biological sample or solution; and

d) measuring the quantity of the corresponding non-deuterated analog inthe biological sample with said calibrated measuring device; and

e) determining the concentration of the corresponding non-deuteratedanalog in the solution of sample using the correlation between detectedquantity and concentration obtained for a compound of Formula I.

Measuring devices that can distinguish the corresponding non-deuteratedanalog from a compound of Formula I include any measuring device thatcan distinguish between two compounds that differ from one another inisotopic abundance. Exemplary measuring devices include a massspectrometer, NMR spectrometer, or IR spectrometer.

In another embodiment, a method for determining the amount of anon-deuterated analog of a compound of Formula I in a solution or abiological sample is provided, comprising:

-   -   a) adding a known amount of a compound of Formula I to the        solution or biological sample;    -   b) detecting at least one signal for a compound of Formula I and        at least one signal for the corresponding non-deuterated analog        in a measuring device that is capable of distinguishing the two        compounds;    -   c) correlating the at least one signal detected for a compound        of Formula I with the known amount of the compound of Formula I        added to the solution or the biological sample; and    -   d) determining the amount of the corresponding non-deuterated        analog in the solution or biological sample using the        correlation between the at least one signal detected of the        compound of Formula I and the amount added to the solution or        biological sample of a compound of Formula I.

In another embodiment, the invention provides a method of evaluating themetabolic stability of a compound of Formula I comprising the steps ofcontacting the compound of Formula I with a metabolizing enzyme sourcefor a period of time and comparing the amount of the compound of FormulaI with the metabolic products of the compound of Formula I after theperiod of time.

In a related embodiment, the invention provides a method of evaluatingthe metabolic stability of a compound of Formula I in a subjectfollowing administration of the compound of Formula I. This methodcomprises the steps of obtaining a serum, blood, tissue, urine or fecessample from the subject at a period of time following the administrationof the compound of Formula I to the subject; and comparing the amount ofthe compound of Formula I with the metabolic products of the compound ofFormula I in the serum, blood, tissue, urine or feces sample.

The present invention also provides kits for use to treat pseudobulbardisorder, diabetic neuropathy, Rett syndrome (RTT); voice disorders dueto uncontrolled laryngeal muscle spasms, including e.g., abductorspasmodic dysphonia, adductor spasmodic dysphonia, muscular tensiondysphonia, and vocal tremor; methotrexate neurotoxicity; and fatiguecaused by cancer. These kits comprise (a) a pharmaceutical compositioncomprising a compound of Formula I or a salt thereof, wherein saidpharmaceutical composition is in a container; and (b) instructionsdescribing a method of using the pharmaceutical composition to treatpseudobulbar affect; diabetic neuropathy; Rett syndrome (RTT); voicedisorders due to uncontrolled laryngeal muscle spasms, including e.g.,abductor spasmodic dysphonia, adductor spasmodic dysphona, musculartension dysphonia, and vocal tremor; methotrexate neurotoxicity; andfatigue caused by cancer.

The container may be any vessel or other sealed or sealable apparatusthat can hold said pharmaceutical composition. Examples include bottles,ampules, divided or multi-chambered holders bottles, wherein eachdivision or chamber comprises a single dose of said composition, adivided foil packet wherein each division comprises a single dose ofsaid composition, or a dispenser that dispenses single doses of saidcomposition. The container can be in any conventional shape or form asknown in the art which is made of a pharmaceutically acceptablematerial, for example a paper or cardboard box, a glass or plasticbottle or jar, a re-sealable bag (for example, to hold a “refill” oftablets for placement into a different container), or a blister packwith individual doses for pressing out of the pack according to atherapeutic schedule. The container employed can depend on the exactdosage form involved, for example a conventional cardboard box would notgenerally be used to hold a liquid suspension. It is feasible that morethan one container can be used together in a single package to market asingle dosage form. For example, tablets may be contained in a bottle,which is in turn contained within a box. In on embodiment, the containeris a blister pack.

The kits of this invention may also comprise a device to administer orto measure out a unit dose of the pharmaceutical composition. Suchdevice may include an inhaler if said composition is an inhalablecomposition; a syringe and needle if said composition is an injectablecomposition; a syringe, spoon, pump, or a vessel with or without volumemarkings if said composition is an oral liquid composition; or any othermeasuring or delivery device appropriate to the dosage formulation ofthe composition present in the kit.

In an embodiment of the kits of this invention, the compositioncomprising the second active agent may be in a vessel or container thatis separate from the vessel containing the composition comprising acompound of Formula I.

EXAMPLES Example 1 Synthesis of(+)-3-(Ethoxy-d₅)-17-(methyl-d₃)-(9α,13α,14α)-morphinan hydrochloride(100)

Compound 100 was prepared as outlined below. Details of the synthesisfollow.

Synthesis of (+)-3-methoxy-17-methyl-(9α,13α,14α)-morphinan (free base,8)

To a reaction vessel was added(+)-3-methoxy-17-methyl-(9α,13α,14α)-morphinan, HBr salt (7; 3.00 g, 8.5mmol), NH₃ in CH₃OH (2.0 M, 8.5 mL, 17.0 mmol), and a stir bar. Thereaction mixture was stirred at RT for 1 h. The resulting material wasconcentrated on a rotary evaporator, then diluted with CHCl₃ (50 mL) andH₂O (50 mL). The layers were separated and the water layer was extractedwith CHCl₃ (50 mL). The combined organic layers were dried overmagnesium sulfate, filtered and concentrated on a rotary evaporator toyield 2.88 g of 8 as a fluffy white solid.

¹H-NMR (300 MHz, CDCl₃): δ 1.12 (ddd, J₁=24.7, J₂=12.6, J₃=3.8, 1H),1.23-1.43 (m, 5H), 1.49-1.52 (m, 1H), 1.62-1.65 (m, 1H), 1.72 (td,J₁=12.6, J₂=4.9, 1H), 1.81 (dt, J₁=12.6, J₂=3.3, 1H), 2.07 (td, J₁=12.6,J₂=3.3, 1H), 2.33-2.47 (m, 5H), 2.57 (dd, J₁=18.1, J₂=5.5, 1H), 2.79(dd, J₁=5.5, J₂=3.3, 1H), 2.98 (d, J=18.1, 1H), 6.68 (dd, J₁=8.2,J₂=2.7, 1H), 6.80 (d, J=2.7, 1H), 7.02 (d, J=8.8, 1H).

Synthesis of (+)-3-methoxy-(9α,13α,14α)-morphinan (9)

The solid (+)-3-methoxy-17-methyl-(9α,13α,14α)-morphinan (8; 6.79 g,25.1 mmol) was placed in a reaction vessel with CHCl₃ and a stir bar.K₂CO₃ (13.85 g, 100.2 mmol) was added and the mixture was stirred at RTunder an atmosphere of N₂ for 10 min before the addition of acetylchloride (7.866 g, 100.2 mmol). The resulting reaction mixture, stillunder an atmosphere of N₂, was stirred under reflux conditions for 7 h,then filtered through a pad of celite. The organic filtrate wasconcentrated on a rotary evaporator and the resulting crude material wasdissolved in CH₃OH then stirred under reflux conditions for 1 h. Thesolution was concentrated on a rotary evaporator then dried under vacuumto yield 6.78 g of 9 as an off-white solid.

¹H-NMR (300 MHz, CDCl₃): δ 1.04-1.13 (m, 1H), 1.19-1.29 (m, 1H),1.37-1.66 (m, 6H), 2.37 (d, J=13.5, 2H), 2.54 (bs, 1H), 2.80 (s, 2H),2.95-2.99 (m, 1H), 3.12-3.18 (m, 2H), 3.48 (s, 1H), 3.71 (s, 3H), 6.76(dd, J₁=8.3, J₂=2.6, 1H), 6.80 (d, J=2.3, 1H), 7.07 (d, J=8.3, 1H).

Synthesis of (+)-17-ethylcarbamate-3-methoxy-(9α,13α,14α)-morphinan (10)

To a reaction vessel fit with a stirbar was added 9 (6.025 g, 2.48 mmol)dissolved in CHCl₃ (100 mL). Diisopropylethylamine (DIEA; 16.32 g, 126.3mmol) was added and the mixture was stirred for 10 min at roomtemperature under nitrogen before the addition of ethylchloroformate(13.094 g, 76.8 mmol). The reaction mixture was stirred under refluxconditions under nitrogen for 3 h, at which point TLC (20%ethylacetate/hexane) showed complete consumption of the startingmaterial. The organic layer was removed and washed first with 1M HCl,and then with saturated NaHCO₃. The aqueous layers from each wash werecombined and back extracted with 50 ml of CHCl₃. The organic layer fromthe back extraction was combined with the organic layer from the washesand the combined organic layers were dried over Na₂SO₄. The organicsolution was then filtered, concentrated on a rotary evaporator then waspurified via automated flash column chromatography (0-30%ethylacetate/hexane) to yield 5.37 g of 10 as a clear light yellow oil.

¹H-NMR (300 MHz, CDCl₃): δ 1.06 (ddd, J₁=25.3, J₂=12.6, J₃=3.8, 1H),1.21-1.39 (m, 7H), 1.45-1.60 (m, 3H), 1.65-1.70 (m, 2H), 2.34-2.37 (m,1H), 2.54-2.69 (m, 2H), 3.04-3.12 (m, 1H), 3.78 (s, 3H), 3.86 (ddd,J₁=42.3, J₂=13.7, J₃=3.8, 1H), 4.12 (q, J=7.14, 2H), 4.31 (dt, J₁=56.6,J₂=4.3, 1H), 6.71 (dd, J₁=8.8, J₂=2.2, 1H), 6.82 (d, J=2.7, 1H), 7.00(apparent t, J=8.2, 1H).

Synthesis of (+)-17-ethylcarbamate-3-hydroxy-(9α,13α,14α)-morphinan (11)

In a reaction vessel fit with a stirbar the carbamate 10 (2.43 g, 7.4mmol) was dissolved in CH₂CH₂ (20 mL) and the resulting solution wascooled to 0° C. BBr₃ (9.24 g, 36.9 mmol) was added and the reactionmixture was stirred under an atmosphere of N₂ at 0° C. for 20 min (atwhich time tlc in 20% ethylacetate/hexane showed the reaction to becomplete). A solution of 27% NH₄OH in ice was placed in a beaker with astir bar and the reaction mixture was slowly added with stirring. Theresulting mixture was stirred for 20 min then was extracted with 4:1CHCl₃/CH₃OH (200 mL). The organic layer was dried over Na₂SO₄, filtered,then concentrated on a rotary evaporator. The crude material waspurified via automated flash column chromatography (CH₃OH with 1%NH₄OH/CHCl₃, 0-10%). The pure fractions were concentrated on a rotaryevaporator to yield 1.48 g of 11 as a white solid.

¹H-NMR (300 MHz, CDCl₃): δ 1.04-1.12 (m, 1H), 1.22-1.36 (m, 7H),1.45-1.59 (m, 3H), 1.63-1.67 (m, 2H), 2.30-2.33 (m, 1H), 2.52-2.66 (m,2H), 3.06 (dt, J₁=18.4, J₂=5.9, 1H), 3.84 (ddd, J₁=35.8, J₂=13.8,J₃=6.1, 1H), 4.10-4.18 (m, 2H), 4.31 (dt, J₁=53.9, J₂=3.1, 1H), 6.64 (m,1H), 6.78 (s, 1H), 6.93 (apparent t, J=7.8, 1H).

Synthesis of (+)-3-(ethoxy-d₅)-17-ethoxycarbonyl-(9α,13α,14α)-morphinan(20)

To a solution of alcohol 11 (1.50 g, 4.8 mmol) in DMF (25 mL), was addedK₂CO₃ (2.00 g, 14.5 mmol, 3.05 eq) and iodoethane-d₅ (1.15 g, 7.1 mmol,1.50 eq) with stirring. The reaction mixture was stirred overnight atroom temperature (rt) under an atmosphere of N₂, was quenched by theaddition of H₂O, and extracted with Et₂O (3×30 mL). The combinedorganics were dried over Na₂SO₄, filtered and concentrated in vacuo to ayellow oil. Purification via automated flash column chromatography(0-40% EtOAc/hexanes) afforded intermediate 20 (1.53 g, 91% yield).

Synthesis of (+)-3-(ethoxy-d₅)-17-(methyl-d₃)-(9α,13α,14α)-morphinanhydrochloride (100)

To a slurry of LiAlD₄ (0.184 g, 4.4 mmol, 2.0 eq) in THF (10 mL)stirring at −78° C. was added a solution of the carbamate 20 (0.763 g,2.2 mmol) in THF (5 mL). After 1 h of stirring at rt, no reaction wasdetected by tlc and an additional 2.0 eq of LiAlD₄ (0.184 g, 4.4 mmol,2.0 eq) was added. The reaction mixture was stirred overnight at rt,then was quenched by the addition of magnesium sulfate heptahydrateuntil cessation of gas evolution. The mixture was filtered, concentratedin vacuo and the resultant crude material was purified via automatedflash column chromatography (CHCl₃/CH₃OH/NH₃OH—90/10/1) to yield thefree amine 100. This material was dissolved in 1.25 M HCl in CH₃OH thenwas concentrated under reduced pressure and dried under high vacuum toyield 14.3 mg of product 100 as the HCl salt.

¹H-NMR (300 MHz, DMSO-d₆): δ 0.94-1.63 (m, 8H), 1.72-1.80 (m, 1H), 1.94(d, J=11.9, 1H), 2.43-2.47 (m, 1H), 2.96 (dd, J₁=19.2, J₂=6.1, 2H),3.09-3.17 (m, 2H), 3.57-3.61 (m, 1H), 6.79-6.82 (m, 2H), 7.11 (d, J=8.8,1H), 9.58 (br s, 1H). HPLC (method: 150 mm C18-RP column-gradient method5-95% ACN; Wavelength: 280 nm): retention time: 3.08 min, purity: 95%.MS (M+H): 294.2.

Example 2 Synthesis of(+)-3-(Ethoxy-d₅)-17-methyl-(9α,13α,14α)-morphinan hydrochloride (104)

Compound 104 was prepared as outlined in Example 1 above with theexception that LiAlH₄ was used in place of LiAlD₄ for the reduction ofthe carbamate 20 to 104.

Synthesis of (+)-3-(ethoxy-d₅)-17-methyl-(9α,13α,14α)-morphinanhydrochloride (104)

To a slurry of LiAlH₄ (0.166 g, 4.4 mmol, 2.0 eq) in THF (10 mL)stirring at −78° C. was added a solution of the carbamate 20 (0.763 g,2.2 mmol) in THF (5 mL). After 1 h an additional 2.0 eq of LiAlH₄ (0.184g, 4.4 mmol, 2.0 eq) was added. The reaction mixture was stirredovernight at rt, then was quenched by the addition of magnesium sulfateheptahydrate until cessation of gas evolution. The mixture was filtered,concentrated in vacuo and the resultant crude material was purified viaautomated flash column chromatography (CHCl₃/CH₃OH/NH₃OH—90/10/1) toyield the free-amine 104. This material was dissolved in 1.25 M HCl inCH₃OH then was concentrated under reduced pressure and dried under highvacuum to yield 31 mg of product 104 as the HCl salt.

¹H-NMR (300 MHz, DMSO-d₆): δ 0.94-1.64 (m, 8H), 1.74-1.82 (m, 1H), 1.97(d, J=12.4, 1H), 2.44-2.47 (m, 1H), 2.81 (s, 3H), 2.96 (dd, J₁=20.0,J₂=5.8, 2H), 3.09-3.18 (m, 2H), 3.55-3.62 (m, 1H), 6.79-6.82 (m, 2H),7.12 (d, J=9.1, 1H), 9.68 (br s, 1H). HPLC (method: 150 mm C18-RPcolumn-gradient method 5-95% ACN; Wavelength: 280 nm): retention time:3.00 min, purity: 95%. MS (M+H): 291.2.

Example 3 Synthesis of(+)-3-(Isopropoxy-d₇)-17-(methyl-d₃)-(9α,13α,14α)-morphinan (102)

Compound 102 was prepared as outlined below. Details of the synthesisfollow.

Synthesis of(+)-3-(isopropoxy-d₇)-17-ethoxycarbonyl-(9α,13α,14α)-morphinan (21)

To a solution of alcohol 11 (1.50 g, 4.8 mmol; produced according toExample 1) in DMF (25 mL), was added K₂CO₃ (2.00 g, 14.5 mmol, 3.05 eq)and 2-iodopropane-d₇ (0.71 mL, 7.1 mmol, 1.50 eq) with stirring. Thereaction mixture was stirred overnight at room temperature (rt) under anatmosphere of N₂, was quenched by the addition of H₂O, and extractedwith Et₂O (3×30 mL). The combined organics were dried over Na₂SO₄,filtered and concentrated in vacuo to a colorless oil. Purification viaautomated flash column chromatography (0-40% EtOAc/hexanes) affordedintermediate 21 (1.48 g, 85% yield).

Synthesis of (+)-3-(isopropoxy-d₇)-17-(methyl-d₃)-(9α,13α,14α)-morphinan(102)

To a slurry of LiAlD₄ (0.340 g, 8.1 mmol, 4.0 eq) in THF (10 mL)stirring at −78° C. was added a solution of the carbamate 21 (0.739 g,2.0 mmol) in THF (5 mL). The reaction mixture was stirred overnight atrt, then was quenched by the addition of magnesium sulfate heptahydrateuntil cessation of gas evolution. The mixture was filtered, the filtrateconcentrated in vacuo and the resultant material was dissolved in CH₃OH.The resulting solution was acidified to pH 4 with fumaric acid resultingin salt precipitation. The mixture was stirred for 5 min, and Et₂O wasadded to bring remaining salt out of solution. The salt was isolated byfiltration and dried to yield 660 mg of final product 102 as the fumaricacid salt.

¹H-NMR (300 MHz, CDCl₃): δ 1.10 (qd, J₁=12.6, J₂=3.8, 1H), 1.21-1.68 (m,7H), 2.01 (td, J₁=13.6, J₂=4.5, 1H), 2.16-2.21 (m, 1H), 2.32-2.47 (m,2H), 2.99-3.01 (m, 2H), 3.10-3.13 (m, 1H), 3.44-3.46 (m, 1H), 6.72 (dd,J₁=8.4, J₂=2.4, 1H), 6.79 (d, J=2.5, 1H), 6.82 (s, 1H), 7.03 (d, J=8.3,1H). HPLC (method: 150 mm C18-RP column-gradient method 5-95% ACN;Wavelength: 280 nm): retention time: 3.11 min, purity: 95%. MS (M+H):310.3.

Example 4 Synthesis of(+)-3-(Isopropoxy-d₇)-17-methyl-(9α,13α,14α)-morphinan (106)

Compound 106 was prepared as outlined in Example 3 above with theexception that LiAlH₄ was used in place of LiAlD₄ for the reduction ofthe carbamate 21 to 106.

Synthesis of (+)-3-(isopropoxy-d₇)-17-methyl-(9α,13α,14α)-morphinan(106)

To a slurry of LiAlH₄ (0.308 g, 8.1 mmol, 4.0 eq) in THF (10 mL)stirring at −78° C. was added a solution of the carbamate 21 (0.739 g,2.0 mmol) in THF (5 mL). The reaction mixture was stirred overnight atrt, then was quenched by the addition of magnesium sulfate heptahydrateuntil cessation of gas evolution. The mixture was filtered, the filtrateconcentrated in vacuo and the resultant material was dissolved in CH₃OH.The resulting solution was acidified to pH 4 with fumaric acid resultingin salt precipitation. The mixture was stirred for 5 min, and Et₂O wasadded to bring remaining salt out of solution. The salt was isolated byfiltration and dried to yield 330 mg of final product 106 as the fumaricacid salt.

¹H-NMR (300 MHz, CDCl₃): δ 1.09 (qd, J₁=12.6, J₂=3.8, 1H), 1.22-1.58 (m,6H), 1.65 (d, J=12.6, 1H), 2.06 (td, J₁=13.5, J₂=4.3, 1H), 2.20 (d,J=12.4, 1H), 2.35 (d, J=13.3, 1H), 2.46-2.53 (m, 1H), 2.78 (s, 3H),2.96-3.12 (m, 2H), 3.25-3.30 (m, 1H), 3.62-3.64 (m, 1H), 6.73 (dd,J₁=8.3, J₂=2.5, 1H), 6.80 (d, J=2.5, 1H), 6.86 (s, 2H), 7.05 (d, J=8.3,1H). HPLC (method: 150 mm C18-RP column-gradient method 5-95% ACN;Wavelength: 280 nm): retention time: 3.18 min, purity: 95%. MS (M+H):307.4.

Example 5 Synthesis of(+)-3-(Methyl-d₃)-17-methyl-(9α,13α,14α)-morphinan (108)

Compound 108 was prepared as outlined below. Details of the synthesisare set forth below.

Synthesis of(+)-17-ethylcarbamate-3-trifluoromethylsulfonyloxy-(9α,13α,14α)-morphinan(22)

To a solution of 11 (9 g, 28.6 mmol, see Example 1) and triethylamine(16 mL, 114 mmol) in CH₂Cl₂ (400 mL) was addedN-phenyl-trifluoromethanesulfonimide “PhNTf₂” (20.7 g, 57.2 mmol) withcooling in an ice-bath. The reaction mixture was allowed to warm toambient temperature and was stirred overnight. The mixture was dilutedwith CH₂Cl₂ (500 mL) and the solution was washed with saturated sodiumbicarbonate, water, and brine, then dried over sodium sulfate. Afterfiltration and concentration under reduced pressure, the crude productwas purified by column chromatography on silica gel (ethylacetate/heptanes, 0-10%) to afford 12 g (94%) of 22 as clear oil.

Synthesis of (+)-17-ethylcarbamate-3-(methyl-d₃)-(9α,13α,14α)-morphinan(23)

To a solution of 22 (22 g, 43.8 mmol) in THF (500 mL) was addedN-methyl-2-pyrrolidone “NMP” (26.2 mL, 153.1 mmol) at ambienttemperature. The reaction mixture was degassed by N₂ purge for 10minutes. Iron(III) acetylacetonate “Fe(acac)₃” (1.65 g, 4.4 mmol) andCD₃MgI (1M in Et₂O, 53 mL, 47.6 mmol, Sigma Aldrich, 99 atom % D) wereadded and the reaction mixture was heated to reflux overnight. Thereaction was cooled and water (500 mL) was added. The layers wereseparated and the aqueous layer was extracted with CH₂Cl₂ (3×100 mL).The combined organics were washed with brine, dried over sodium sulfate,filtered, concentrated under reduced pressure and purified by columnchromatography on silica gel (ethyl acetate/heptanes, 0-10%) to afford 4g (94%, based on recovered starting material) of 23 and 16 g ofrecovered 22.

Synthesis of (+)-3-(methyl-d₃)-17-methyl-(9α,13α,14α)-morphinan (108)

A mixture of 23 (1.5 g, 4.8 mmol) in THF (70 mL) was treated with LiAlH₄(1M in THF, 19.2 mL) at 0° C. The mixture was allowed to warm to ambienttemperature and was stirred overnight. Water (1 mL) was added to quenchthe reaction, followed by NaOH (24%, 10 mL). The mixture was stirred for30 minutes, during which time white solid precipitated. The solid wasfiltered and the filtrate was concentrated under reduced pressure. Thecrude product was purified by preparative HPLC (see conditions describedbelow) to afford 108. The free amine was dissolved in MTBE (30 mL) andheated to reflux. H₃PO₄ (in isopropanol) was added dropwise, resultingin the formation of a white solid. The addition of H₃PO₄ was continueduntil no more white solid appeared to precipitate. The solid wasfiltered and washed with MTBE (100 mL) to provide 1.2 g of solid. Thematerial was recrystallized with MeOH/MTBE to provide 108 as thephosphate salt (0.75 g, 47%).

¹H-NMR (300 MHz, CD₃OD): δ 1.07-1.57 (m, 8H), 1.69-1.72 (m, 1H),1.96-2.10 (m, 2H), 2.56 (br.d., 1H), 2.91 (s, 3H), 3.06-3.11 (br. s. andm, 3H), 3.56 (br.m., 1H), 7.03-7.18 (m, 3H). HPLC (method: 20 mm C-18 RPcolumn-gradient method 2-95% ACN/water/0.1% formic acid; Wavelength: 210nm): retention time: 2.59 min, purity: 99.4%. MS (M+H): 259.2

Preparative HPLC Conditions:

Sunfire C18 5 um 30×150 mm column; Waters GI Pump;

Solvent A=water; Solvent B=acetonitrile

Gradient:

Time (min) Flow Rate (mL/min) % A % B 0 40.00 90 10 7.00 40.00 50 508.00 40.00 5 95 9.00 20.00 90 10 10.00 20.00 90 10

Example 6 Synthesis of(+)-3-Methyl-17-(methyl-d₃)-(9α,13α,14α)-morphinan (109)

Compound 109 was prepared as outlined below. Details of the synthesisfollow.

Synthesis of (+)-17-ethylcarbamate-3-methyl-(9α,13α,14α)-morphinan (24)

To a solution of 22 (3.6 g, 7.16 mmol, see Example 5) in THF (100 mL)was added N-methyl-2-pyrrolidone “NMP” (4.3 mL, 25.1 mmol) at ambienttemperature. The reaction mixture was degassed by N₂ purge for 10minutes. Iron(III) acetylacetonate “Fe(acac)₃” (270 mg, 0.72 mmol) andMeMgBr (3M in Et₂O, 2.9 mL, 7.8 mmol) were added and the reactionmixture was heated to reflux overnight. The reaction was cooled andwater (50 mL) was added. The layers were separated and the aqueous layerwas extracted with CH₂Cl₂ (3×100 mL). The combined organics were washedwith brine, dried over sodium sulfate, filtered, concentrated underreduced pressure, and purified by column chromatography on silica gel(ethyl acetate/heptanes, 0-10%) to give 0.84 g of 24 (75% based onrecovered starting material) and 2 g of recovered 22.

Synthesis of (+)-3-methyl-17-(methyl-d₃)-(9α,13α,14α)-morphinan (109)

A mixture of 24 (1 g, 6.2 mmol) in THF (30 mL) was treated with LiAlD₄(0.9 g, 24.8 mmol, Cambridge Isotopes, 98 atom % D) at 0° C. and thereaction was allowed to warm to ambient temperature and stir overnight.Water (1 mL) was added to quench the reaction, followed by NaOH (24%, 5mL). The mixture was stirred for 30 minutes, during which time whitesolid precipitated. The solid was filtered and the filtrate wasconcentrated under reduced pressure. The crude product was dissolved inEtOAc (30 mL) and extracted with 10% HCl (3×30 mL). The combined aqueouslayer was washed with CH₂Cl₂ (30 mL) and neutralized with 10% NaOH. Theaqueous layer was then extracted with CH₂Cl₂ (3×30 mL), the combinedorganics were dried over sodium sulfate, filtered and concentrated underreduced pressure to afford 109. The free amine was dissolved in MTBE (30mL) and heated to reflux. H₃PO₄ (in isopropanol) was added dropwise,resulting in the formation of a white solid. The addition of H₃PO₄ wascontinued until no more white solid appeared to precipitate. The solidwas filtered and washed with MTBE (100 mL). The product wasrecrystallized with MeOH/MTBE to provide 109 as the phosphate salt (0.4g, 36%).

¹H-NMR (300 MHz, CD₃OD): δ 1.09-1.60 (m, 7H), 1.68-1.71 (m, 1H),1.98-2.02 (m, 1H), 2.04-2.15 (m, 1H), 2.31 (s, 3H), 2.50-2.55 (m, 1H),2.64-2.65 (m, 1H), 3.06-3.07 (m, 1H), 3.16 (br.s., 2H), 3.54-3.55 (m,1H), 7.02-7.17 (m, 3H). ¹³C-NMR (75 MHz, CD₃OD): δ 20.2, 21.7, 25.8,35.0, 35.8, 60.3, 125.8, 127.4, 128.0, 130.8, 137.2, 137.4. HPLC(method: 20 mm C18 RP column-gradient method 2-95% ACN/water/0.1% formicacid; Wavelength: 210 nm):—retention time: 2.51 min. purity: 97.7%. MS(M+H): 259.2.

Example 7 Synthesis of(+)-3-(Methyl-d₃)-17-(methyl-d₃)-(9α,13α,14α)-morphinan (110)

Compound 110 was prepared as outlined below. Details of the synthesisfollow.

Synthesis of (+)-3-(methyl-d₃)-17-(methyl-d₃)-(9α,13α,14α)-morphinan(110)

A mixture of 23 (2.5 g, 8 mmol, see Example 5) in THF (70 mL) wastreated with LiAlD₄ (1.7 g, 32 mmol, Cambridge Isotopes, 98 atom % D) at0° C. The mixture was allowed to warm to ambient temperature and wasstirred overnight. Water (1 mL) was added to quench the reaction,followed by NaOH (24%, 10 mL). The mixture was stirred for 30 minutes,during which time white solid precipitated. The solid was filtered andthe filtrate was concentrated under reduced pressure. The crude productwas purified by preparative HPLC (see conditions described in Example 5)to provide 110. The free amine was dissolved in MTBE (50 mL) and washeated to reflux. H₃PO₄ (in isopropanol) was added dropwise, resultingin the formation of a white solid. The addition of H₃PO₄ was continueduntil no more white solid appeared to precipitate. The solid wasfiltered and washed with MTBE (100 mL) to provide 1.2 g of solid. Theproduct was recrystallized in MeOH/MTBE to provide 110 as the phosphatesalt (1 g, 36%).

¹H-NMR (300 MHz, CD₃OD): δ 1.09-1.13 (m, 1H), 1.24-1.33 (m, 1H),1.39-1.72 (m, 6H), 1.95-2.04 (m, 1H), 2.16-2.18 (m, 1H), 2.50-2.54 (m,1H), 2.60-2.68 (m, 1H), 3.07-3.16 (m. and s., 3H), 3.54-3.55 (m, 1H),7.02-7.17 (m, 3H). ¹³C-NMR (75 MHz, D₂O): δ 21.4, 23.2, 25.5, 25.6,34.7, 39.3, 43.0, 47.8, 60.4, 126.4, 127.5, 128.3, 131.2, 138.0. HPLC(method: 20 mm C18 RP column-gradient method 2-95% ACN/water/0.1% formicacid; Wavelength: 210 nm): retention time: 2.61 min., purity >99.9%. MS(M+H): 262.2.

Example 8 Evaluation of Metabolic Stability in CYP2D6 SUPERSOMES™

Human CYP2D6 SUPERSOMES™ were purchased from GenTest (Woburn, Mass.,USA). 7.5 mM stock solutions of test compounds (Compounds 100, 102, 104,106, dextromethorphan, a deuterated analog of dextromethorphan whereineach methyl group was replaced with CD₃ (“d₆-dextromethorphan”, chemicalname (+)-3-d₃-methoxy-17-d₃-methyl-(9α,13α,14α)-morphinan, also referredto as Compound 101 in U.S. Ser. No. 12/112,936, and as “Test Compound”in FIG. 1 and Table 2 below), the ethyl ether analog of dextromethorphan(“dextroethorphan”) or the isopropyl ether analog of dextromethorphan(“dextroisoproporphan”)) were prepared in DMSO. The 7.5 mM stocksolutions were diluted to 50 μM in acetonitrile (ACN). The 1000 pmol/mLCYP2D6 supersomes were diluted to 62.5 pmol/mL in 0.1 M potassiumphosphate buffer, pH 7.4, containing 3 mM MgCl₂. The diluted SUPERSOMES™were added to wells of a 96-well deep-well polypropylene plate intriplicate. 10 μL of the 50 μM test compound was added to the supersomesand the mixture was pre-warmed for 10 minutes. Reactions were initiatedby addition of pre-warmed NADPH solution. The final reaction volume was0.5 mL and contained 50 pmol/mL CYP2D6 SUPERSOMES™, 1 μM test compound,and 2 mM NADPH in 0.1 M potassium phosphate buffer, pH 7.4, and 3 mMMgCl₂. The reaction mixtures were incubated at 37° C. and 50 μL aliquotswere removed at 0, 5, 10, 20, and 30 minutes and added to shallow-well96-well plates which contained 50 μL of ice-cold ACN with internalstandard to stop the reactions. The plates were stored at 4° C. for 20minutes after which 100 μL of water was added to the wells of the platebefore centrifugation to pellet precipitated proteins. Supernatants weretransferred to another 96-well plate and analyzed for amounts of parentremaining by LC-MS/MS using an Applied Bio-systems API 4000 massspectrometer.

The in vitro half-life (t_(1/2)) for each of the test compounds wascalculated from the slopes of the linear regression of % parentremaining (ln) vs incubation time relationship: in vitrot_(1/2)=0.693/k, where k=−[slope of linear regression of % parentremaining(ln) vs incubation time]. Data analysis was performed usingMicrosoft Excel Software.

FIG. 1 and Table 2, below, show the results of the SUPERSOMES™experiment. Note that in FIG. 1, the curves for Compounds 100 and 104overlap one another. “Test Compound” in FIG. 1 and Table 2 refers todeuterated dextromethorphan (“d6-dextromethorphan”,(+)-3-d3-methoxy-17-d3-methyl-(9α,13α,14α)-morphinan, which is alsoreferred to as Compound 101 in U.S. Ser. No. 12/112,936, incorporated byreference herein).

TABLE 2 Calculated Half-life in SUPERSOMES ™. Compound t_(1/2) ± SD(min) Dextromethorphan  1.7 ± 0.3 Test Compound  5.6 ± 1.5Dextroethorphan 10.3 ± 2.1 Dextroisoproporphan 21.7 ± 1.6 Compound 10636.0 ± 2.8 Compound 102 39.0 ± 1.9 Compound 104 49.1 ± 4.1 Compound 10051.3 ± 3.7

Each of the deuterated compounds tested demonstrated a longer half-lifewhen incubated with CYP2D6 SUPERSOMES™ than any of the correspondingundeuterated test compounds or a deuterated version of dextromethorphan(Test Compound). Thus, in this assay, the compounds of this inventionwere more resistant to metabolism than dextromethorphan or deuterateddextromethorphan (Test Compound).

Example 9 Determination of Metabolic Stability of Test Compounds UsingHuman Liver Microsomes

Human liver microsomes (20 mg/mL) were obtained from Xenotech, LLC(Lenexa, Kans.). β-nicotinamide adenine dinucleotide phosphate, reducedform (NADPH), magnesium chloride (MgCl₂), and dimethyl sulfoxide (DMSO)were purchased from Sigma-Aldrich.

7.5 mM stock solutions of test compounds were prepared in DMSO. The 7.5mM stock solutions were diluted to 50 μM in acetonitrile (ACN). The 20mg/mL human liver microsomes were diluted to 1.25 mg/mL (1 mg/mL final)in 0.1 M potassium phosphate buffer, pH 7.4, containing 3 mM MgCl₂. Thediluted microsomes (375 μL) were added to wells of a 96-wellpolypropylene plate in triplicate. 10 μL of the 50 μM test compound wasadded to the microsomes and the mixture was pre-warmed for 10 minutes.Reactions were initiated by addition of 125 μL of pre-warmed NADPHsolution. The final reaction volume was 0.5 mL and contained 1.0 mg/mLhuman liver microsomes, 1 μM test compound, and 2 mM NADPH in 0.1 Mpotassium phosphate buffer, pH 7.4, and 3 mM MgCl₂. The reactionmixtures were incubated at 37° C., and 50 μL aliquots were removed at 0,5, 10, 20, and 30 minutes and added to shallow 96-well plates whichcontained 50 μL of ice-cold ACN with internal standard to stop thereactions. The plates were stored at 4° C. for 20 minutes after which100 μL of water was added to the wells of the plate beforecentrifugation to pellet precipitated proteins. Supernatants weretransferred to another 96-well plate and analyzed for amounts of parentremaining by LC-MS/MS using an Applied Bio-systems API 4000 massspectrometer.

7-ethoxy coumarin was used as a positive control.

The in vitro t_(1/2)s for test compounds were calculated from the slopesof the linear regression of % parent remaining (ln) vs incubation timerelationship:in vitro t _(1/2)=0.693/k,where k=−[slope of linear regression of % parent remaining(ln) vsincubation time]Data analysis was performed using Microsoft Excel Software.

FIG. 2 (panels A and B), FIG. 3, Table 3, and Table 4 show the resultsof this experiment.

TABLE 3 Calculated Half-life in Human Liver Microsomes Change overt_(1/2) ± SD non-deuterated Compound (min) compound Dextroethorphan 28.3± 0.6 n/a Compound 104 59.1 ± 2.2 109% Compound 100 59.2 ± 1.7 109%Dextroisoproporphan 36.1 ± 1.6 n/a Compound 106 68.8 ± 0.9  91% Compound102 61.0 ± 0.4  69%

In the case of both dextroethorphan and dextroisoproporphan, deuterationof the alkyl ether (R¹) resulted in a significant increase in half life(t_(1/2)) in human liver microsomes as compared to the undeuteratedcounterpart.

TABLE 4 Calculated Half-life in Human Liver Microsomes Change over Ave.t_(1/2) non-deuterated Compound (n = 2) compound Dimemorfan 23.1 n/aCompound 108 28.0 21% Compound 110 31.6 37%

In the case of dimemorfan, deuteration of R¹ resulted in a significantincrease in half life (t_(1/2)) in human liver microsomes as compared tothe undeuterated counterpart. Deuteration of the N-methyl moiety (R²)caused a further significant increase in t_(1/2).

Without further description, it is believed that one of ordinary skillin the art can, using the preceding description and the illustrativeexamples, make and utilize the compounds of the present invention andpractice the claimed methods. It should be understood that the foregoingdiscussion and examples merely present a detailed description of certainpreferred embodiments. It will be apparent to those of ordinary skill inthe art that various modifications and equivalents can be made withoutdeparting from the spirit and scope of the invention. All the patents,journal articles and other documents discussed or cited above are hereinincorporated by reference.

We claim:
 1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is—(C₁-C₄)alkyl, wherein R¹ is optionally substituted with one or moredeuterium atoms; and R² is selected from CH₃, CH₂D, CHD₂, and CD₃;provided that at least one deuterium atom is present at either R¹ or R².2. The compound of claim 1, wherein R² is CH₃ or CD₃.
 3. The compound ofclaim 1, wherein R¹ is —CH₃, —CD₃, —CH₂CH₃, —CD₂CD₃, —CD₂CH₃, —CH₂CD₃,—CH(CH₃)₂, —CD(CD₃)₂, —CH(CD₃)₂, —CD(CH₃)₂, —CH₂CH(CH₃)₂, —CD₂CH(CH₃)₂,—CH₂CD(CH₃)₂, —CH₂CH(CD₃)₂, —CD₂CD(CH₃)₂, —CD₂CH(CD₃)₂, —CH₂CD(CD₃)₂, or—CD₂CD(CD₃)₂.
 4. The compound of claim 3, wherein R¹ is —CD₃, —CD₂CD₃,—CD₂CH₃, —CH₂CD₃, —CD(CD₃)₂, —CH(CD₃)₂, —CD(CH₃)₂, —CD₂CH(CH₃)₂,—CH₂CD(CH₃)₂, —CH₂CH(CD₃)₂, —CD₂CD(CH₃)₂, —CD₂CH(CD₃)₂, —CH₂CD(CD₃)₂, or—CD₂CD(CD₃)₂.
 5. The compound of claim 4, wherein R¹ is —CD₃, —CD₂CD₃,or —CD₂CD(CD₃)₂.
 6. The compound of claim 5, wherein R¹ is —CD₃.
 7. Thecompound of claim 3, wherein R¹ is —CH₃, —CH₂CH₃, —CH(CH₃)₂, or—CH₂CH(CH₃)₂ and R² is selected from CD₃.
 8. The compound of claim 1,wherein any atom not designated as deuterium is present at its naturalisotopic abundance.
 9. The compound of claim 3, selected from any oneof:

or a pharmaceutically acceptable salt thereof, wherein any atom notdesignated as deuterium is present at its natural isotopic abundance.10. A pyrogen-free pharmaceutical composition comprising the compound ofclaim 1 or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier.
 11. The composition of claim 10,wherein the second therapeutic agent is selected from quinidine,quinidine sulfate, oxycodone, and gabapentin.
 12. The compound of claim1, wherein deuterium incorporation at any atom designated as deuteriumis at least 90%.
 13. The compound of claim 12, wherein deuteriumincorporation at any atom designated as deuterium is at least 95%. 14.The compound of claim 9, wherein deuterium incorporation at any atomdesignated as deuterium is at least 90%.
 15. The compound of claim 14,wherein deuterium incorporation at any atom designated as deuterium isat least 95%.